Karsten Keller

Quality of oral anticoagulation with phenprocoumon in regular medical care and its potential for improvement in a telemedicine-based coagulation service – results from the prospective, multi-center, observational cohort study thrombEVAL

BackgroundThe majority of studies on quality of oral anticoagulation (OAC) therapy with vitamin K-antagonists are performed with short-acting warfarin. Data on long-acting phenprocoumon, which is frequently used in Europe for OAC therapy and is considered to enable more stable therapy adjustment, are scarce. In this study, we aimed to assess quality of OAC therapy with phenprocoumon in regular medical care and to evaluate its potential for optimization in a telemedicine-based coagulation service.MethodsIn the prospective observational cohort study program thrombEVAL we investigated 2,011 patients from regular medical care in a multi-center cohort study and 760 patients from a telemedicine-based coagulation service in a single-center cohort study. Data were obtained from self-reported data, computer-assisted personal interviews, and laboratory measurements according to standard operating procedures with detailed quality control. Time in therapeutic range (TTR) was calculated by linear interpolation method to assess quality of OAC therapy. Study monitoring was carried out by an independent institution.ResultsOverall, 15,377 treatment years and 48,955 international normalized ratio (INR) measurements were analyzed. Quality of anticoagulation, as measured by median TTR, was 66.3% (inte rquartile range (IQR) 47.8/81.9) in regular medical care and 75.5% (IQR 64.2/84.4) in the coagulation service (P <0.001). Stable anticoagulation control within therapeutic range was achieved in 63.8% of patients in regular medical care with TTR at 72.1% (IQR 58.3/84.7) as compared to 96.4% of patients in the coagulation service with TTR at 76.2% [(IQR 65.6/84.7); P = 0.001)]. Prospective follow-up of coagulation service patients with pretreatment in regular medical care showed an improvement of the TTR from 66.2% (IQR 49.0/83.6) to 74.5% (IQR 62.9/84.2; P <0.0001) in the coagulation service. Treatment in the coagulation service contributed to an optimization of the profile of time outside therapeutic range, a 2.2-fold increase of stabile INR adjustment and a significant decrease in TTR variability by 36% (P <0.001).ConclusionsQuality of anticoagulation with phenprocoumon was comparably high in this real-world sample of regular medical care. Treatment in a telemedicine-based coagulation service substantially improved quality of OAC therapy with regard to TTR level, frequency of stable anticoagulation control, and TTR variability.Trial registrationClinicalTrials.gov, unique identifier NCT01809015, March 8, 2013.

Syncope and collapse in acute pulmonary embolism

BACKGROUND Syncope and collapse (=presyncope) are 2 symptoms of pulmonary embolism (PE), which are suspected of being connected with poorer outcome, regardless of haemodynamic instability. However, pathomechanisms are not completely understood. We aimed to investigate these pathomechanisms in regard to blood pressure and heart rate of syncope/collapse in PE. METHODS We performed a retrospective study of consecutive PE patients, who were treated in the Internal Medicine Department. Patients with and without syncope/collapse were compared. Regression models for associations between syncope/collapse and blood pressure, heart rate and shock index (SI) were computed. Moreover we calculated ROC analyses and Youden indices for effectiveness and cut-off-values of these parameters for the probability of syncope/collapse. RESULTS 182 patients (mean-age 68.5±15.3years; 61.5% female) with confirmed PE were included in this study. 20 PE patients (11.0%) showed a syncope/collapse. PE patients with syncope/collapse were in median 7.5years older (78.5 (72.0/82.3) vs. 71.0 (61.0/80.0) years, P=.0575), had lower systolic (132.0 (108.8/154.0) vs. 145.5 (127.0/166.0) mmHg, P=.0845) and diastolic (70.0±27.0 vs. 78.4±18.4mmHg, P=.0740) blood pressure, whereas heart rate (103.5 (87.8/116.0) vs. 90.0 (76.0/102.0)beats/min, P=.0518), SI (0.78 (0.65/1.01) vs. 0.60(0.50/0.79), P=.0127) and frequency of right ventricular dysfunction (RVD) (88.2% vs. 55.8%, P=.0294) were higher in PE patients with syncope/collapse than in those without. Hypotension (systolic blood pressure<90mmHg), tachycardia and SI>1.0were connected with 6.4-fold, 2.5-fold and 5.8-fold higher probability of syncope/collapse, respectively. ROC analyses revealed cut-off values of ≤110mmHg, ≥107beats/min and >0.62 for systolic blood pressure, heart rate and SI with low AUC values, respectively. CONCLUSIONS The pathomechanism of syncope/collapse in patients with acute PE seems to be connected with blood pressure fall, heart rate increase and RVD, in terms of cardiovascular syncope with reduced cardiac output and vasovagal reflex.

Right ventricular dysfunction in hemodynamically stable patients with acute pulmonary embolism

BACKGROUND Echocardiography for risk stratification in hemodynamically stable patients with pulmonary embolism (PE) is well-established. Right ventricular dysfunction (RVD) is associated with an elevated mortality and adverse outcome. The aim of our study was to compare RVD criteria and investigate the role of elevated systolic pulmonary artery pressure (sPAP) in the diagnosis of RVD. METHODS We retrospectively analyzed the echocardiographic and laboratory data of all hemodynamically stable patients with confirmed PE (2006-2011). The data were compared with three different definitions of RVD: Definition 1: RV dilatation, abnormal motion of interventricular septum, RV hypokinesis or tricuspid regurgitation. Definition 2: as with definition 1 but including elevated sPAP (>30mmHg). Definition 3: elevated sPAP (>30mmHg) as single RVD criterion. RESULTS A total number of 129 patients (59.7% women, age 70.0years (60.7/81.0)) were included in this study. Median Troponin I level was measured as 0.02ng/ml (0/0.14); mean sPAP 33.9±18.5mmHg. The troponin cut-off levels for predicting a RVD of the 3 RVD definitions were in definition 1-3: >0.01ng/ml, >0.01ng/ml and >0.00ng/ml. Analysis of the ROC curve showed an AUC for RVD definitions 1-3: 0.790, 0.796 and 0.635. CONCLUSIONS The combination of commonly used RVD criteria with added elevated sPAP improves the diagnosis of RVD in acute PE. Troponin I values of >0.01ng/ml in acute PE point to an RVD.

Evaluation of oral anticoagulation therapy: rationale and design of the thrombEVAL study programme.

Background Since decades, oral anticoagulation (OAC) with vitamin K antagonists (VKA) is an established therapy for both prevention and treatment of thromboembolism in daily clinical routine. Increasing life expectancy, demographic changes, and novel oral anticoagulants have led to an increasing complexity of medical therapy. However, data on quality and management of VKA therapy with phenprocoumon in current medical care are limited. Our aim is to investigate the quality of OAC with VKA in current health care and to evaluate the potential for improvements. Study design The investigator-initiated thrombEVAL study programme comprises two cohorts of patients treated with vitamin K antagonists for oral anticoagulation therapy in real-life settings: a multicentre cohort of patients in regular medical care and a multilocal, single-centre cohort of patients in a telemedicine-based coagulation service. The study programme is expected to enrol a total number of approximately 2000 to 2500 patients. Both cohorts will build on a detailed clinical assessment of participants and anticoagulation therapy at study enrolment. Subsequently active and passive follow-up investigations are carried out to document and validate complications of the treatment. The primary short-term outcome is the distribution of time in therapeutic range; the primary long-term outcome comprises the composite of stroke, systemic embolism, myocardial infarction, major and clinically relevant bleeding, and death. Conclusions The thrombEVAL project will provide a large prospective observational cohort of patients predominantly treated with phenprocoumon. It will evaluate the quality of oral anticoagulation in regular medical care and a telemedicine-based coagulation service.

D-dimer for risk stratification in haemodynamically stable patients with acute pulmonary embolism

PURPOSE Patients with submassive pulmonary embolism (PE) have a higher short-term mortality than those with low-risk PE. Rapid identification of submassive PE is important for adequate treatment of non-massive PE. We aimed to investigate the utility of D-dimer for the prediction of submassive PE stadium in normotensive PE patients. PATIENTS AND METHODS Normotensive PE patients were classified into submassive or low-risk PE groups. In addition to the comparison of the groups, area under the curve (AUC) and D-dimer cut-off for the prediction of submassive PE stadium, multi-variate logistic regression for association between D-dimer values above this cut-off and submassive PE stadium were also calculated. RESULTS The data of 129 normotensive PE patients (59.7% women, mean age 70.0 years (60.7/81.0)) were analysed retrospectively. Patients with submassive PE were older (75.0 years (61.7/81.0) vs. 66.5 years (55.7/74.2), P=0.026) and more frequently female (63.6% vs. 53.8%, P=0.35). Heart rate (100.0beats/min (85.0/108.0) vs. 80.0beats/min (70.0/96.2), P<0.0001), systolic pulmonary-artery pressure (41.55±16.79mmHg vs. 22.62±14.81mmHg, P<0.0001), and D-dimer (2.00mg/l (1.09/3.98) vs. 1.21mg/l (0.75/1.99), P=0.011) were higher in patients with submassive PE. D-dimer values >1.32mg/l were indicative of submassive PE and shock-index ≥0.7. The effectiveness (AUC) of the test was 0.63 for submassive PE and 0.64 for shock-index ≥0.7. D-dimer values >1.32mg/l were associated with submassive PE stadium (OR 3.81 (95% CI: 1.74-8.35), P=0.00083) as well as with systolic blood pressure (OR 0.98 (95% CI: 0.97-0.99), P=0.033), heart rate (OR 1.02 (95% CI: 1.00-1.04), P=0.023) and shock-index value (OR 15.89 (95% CI: 1.94-130.08), P=0.0099). CONCLUSIONS D-dimer values >1.32mg/l are indicative of submassive PE stadium and shock-index ≥0.7. Efficacy of D-dimer for predicting submassive PE stadium was only weak to moderate.

Impact of exaggerated blood pressure response in normotensive individuals on future hypertension and prognosis: Systematic review according to PRISMA guideline

PURPOSE Arterial hypertension (aHT) is the leading risk factor for morbidity and mortality worldwide. Blood pressure (BP) deviation at rest is well defined and accompanies risk for cardiovascular events and cardiovascular mortality. A growing body of evidence emphasises that an exaggerated blood pressure response (EBPR) in cardiopulmonary exercise testing (CPET) could help to identify seemingly cardiovascular healthy and normotensive subjects, who have an increased risk of developing aHT and cardiovascular events in the future. MATERIALS AND METHODS The PubMed online database was searched for published studies reporting exercise-related BP and both the risk of aHT and cardiovascular events in the future. RESULTS We identified 18 original studies about EBPR in CPET, which included a total of 35,151 normotensive individuals for prediction of new onset of aHT in the future and 11 original studies with 43,012 enrolled subjects with the endpoint of cardiovascular events in the future. Although an EBPR under CPET is not well defined, a large number of studies emphasise that EBPR in CPET is associated with both new-onset aHT and cardiovascular events in the future. CONCLUSIONS A growing number of studies support the hypothesis that EBPR in CPET may be a diagnostic tool to identify subjects with an elevated risk of developing aHT and cardiovascular events in the future.

Right bundle branch block and SIQIII-type patterns for risk stratification in acute pulmonary embolism.

INTRODUCTION Risk stratification in acute pulmonary embolism (PE) is crucial for identification of patients with poor prognosis. We aimed to investigate the ECG alterations of right bundle branch block (RBBB) and SIQIII-type patterns for risk stratification in acute PE. MATERIALS AND METHODS Retrospective analysis of PE patients, treated in the Internal Medicine Department, was performed. Patients with RBBB and/or SIQIII-type were compared with those without both patterns. Logistic regression models for association between these ECG alterations and respectively right ventricular dysfunction (RVD), high-risk PE status and myocardial injury were computed. RESULTS 175 patients were included for this retrospective analysis. Total study sample comprised 37 PE patients (21.1%) with RBBB and/or SIQIII-type patterns and 138 PE patients (78.9%) without both signs. Heart rate (97.4±17.2 vs. 93.2±26.8/min, P=0.021), cardiac troponin I values (0.19±0.38 vs. 0.11±0.24, P=0.003) and percentage of patients with RVD (83.9% vs. 52.7%, P=0.005) were significantly higher in PE patients with RBBB and/or SIQIII-type patterns compared to PE patients without both ECG alterations. Multi-variate logistic regression models adjusted for age and gender revealed significant associations between RBBB and RVD (OR3.942, 95% CI1.054-14.747, P=0.042) and between SIQIII-type patterns and RVD (OR5.667, 95% CI1.144-28.071, P=0.034). The association between RBBB and cardiac injury (cTnI>0.4ng/ml) (OR2.531, 95% CI 0.973-6.583, P=0.06) showed a borderline significance, while the association between SIQIII-type patterns and cardiac injury was significant (OR3.956, 95% CI1.309-11.947, P=0.015). CONCLUSIONS RBBB and SIQIII-type patterns were both associated with RV overload and cardiac injury. RBBB and SIQIII-type patterns were connected with 3.9-fold and 5.7-fold elevated risk of RVD, respectively.

Symptoms of depression and anxiety predict mortality in patients undergoing oral anticoagulation: Results from the thrombEVAL study program

BACKGROUND/OBJECTIVES Depression and anxiety are highly prevalent in cardiovascular patients. Therefore, we examined whether the 4-item Patient Health Questionnaire (PHQ-4, measuring symptoms of depression and anxiety) predicts all-cause mortality in outpatients with long-term oral anticoagulation (OAC). METHODS The sample comprised n=1384 outpatients from a regular medical care setting receiving long-term OAC with vitamin K antagonists. At baseline, symptoms of anxiety and depression were assessed with the PHQ-4 and the past medical history was taken. The outcome was all-cause mortality in the 24 month observation period. The median follow-up time was 13.3 months. RESULTS N=191 patients from n=1384 died (death rate 13.8%). Each point increase in the PHQ-4 score was associated with a 10% increase in mortality (hazard ratio [HR] 1.10, 95% confidence interval [95% CI] 1.05-1.16) after adjustment for age, sex, high school graduation, partnership, smoking, obesity, frailty according to the Barthel Index, Charlson Comorbidity Index and CHA2DS2-VASc score. The depression component (PHQ-2) increased mortality by 22% and anxiety (GAD-2) by 11% respectively. Neither medical history of any mental disorder, nor intake of antidepressants, anxiolytics or hypnotics predicted excess mortality. CONCLUSIONS Elevated symptoms of depression and, to a lesser degree, symptoms of anxiety are independently associated with all-cause mortality in OAC outpatients. The PHQ-4 questionnaire provides valuable prognostic information. These findings emphasize the need for implementing regular screening procedures and the development and evaluation of appropriate psychosocial treatment approaches for OAC patients.

Relevance of depression for anticoagulation management in a routine medical care setting: results from the ThrombEVAL study program

Depressive symptoms have detrimental effects on quality of life and mortality. Poor adherence to a treatment regimen is a potential mechanism for the increased risk of adverse medical events associated with depression. Regarding oral anticoagulation with vitamin K antagonists, adherence is crucial for the outcome. Little is known about the clinical relevance of current depressiveness for anticoagulation treatment.

History of deep vein thrombosis is a discriminator for concomitant atrial fibrillation in pulmonary embolism

BACKGROUND Pulmonary embolism (PE) is the consequence of deep vein thrombosis (DVT) in 70% of all cases. Although, PE and DVT are commonly related to risk factors of Virchows triad, both entities are linked to cardiovascular risk factors, but risk factors seem differently important in both entities. OBJECTIVES We aimed to investigate clinical profile and outcome of patients with PE history stratified by concomitant DVT. PATIENTS/METHODS Data from the observational multi-center thrombEVAL-study were analyzed. RESULTS The sample (N=2,318) comprised 295 PE patients, of whom 69.2% (N=204) had DVT. Individuals without DVT were older and had higher prevalence of concomitant atrial fibrillation (AF), chronic lung diseases, coronary artery disease, heart failure and hypertension. Multivariable regression revealed an independent association of AF (Odds Ratio (OR) 3.17, 95% CI 1.63-6.18, P<0.001) and coronary artery disease (OR 2.31, 95% CI 1.15-4.66, P=0.019) with PE without DVT. There was higher frequency of permanent AF in individuals without DVT, whereas paroxysmal AF was more prevalent in individuals with DVT. All AF subtypes were independently associated with PE without DVT with increasing ORs from paroxysmal to permanent AF. PE patients with and without DVT did not differ in survival (P=0.32) and cost-relevant clinical outcome (P=0.26) during follow-up. AF in PE patients was associated with cost-relevant clinical outcome (Hazard Ratio (HR) 1.78, 95% CI 1.03-3.09, P=0.040), but no significant difference in survival (HR 0.93, 95% CI 0.35-2.50, P=0.88) was observed. CONCLUSIONS History of DVT is a significant discriminator for clinical profile of PE patients. Individuals without DVT had more often cardiac and pulmonary disease with strongest association with AF. Data advocate a potential link between AF and PE. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov, Unique identifier NCT01809015.